Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:12][CH2:13][N:9]3[C:10]=2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]3)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[ClH:1].[N:18]1([C:2]2[C:11]3[CH2:12][CH2:13][N:9]4[C:10]=3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]4)=[CH:4][CH:3]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn2c3c(c(Cl)ccc3c1=O)CC2
Solvent: CS(C)=O
Product: Cl
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CC2
Yield: 37.2 %

Procedure:
20 ml of dimethyl sulfoxide was added to a mixture of 3 g of 9-chloro-6-oxo-1,2-dihydro-6H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid and 6 g of anhydrous piperazine and the mixture was heated on an oil bath at 140° to 150° C. for 6 hours. After completion of reaction the solvent was removed therefrom under reduced pressure and 50 ml of water was added to the residue to dissolve it. The solution was shaken with 100 ml of chloroform and the water layer was separated and treated with activated carbon. The aqueous solution was rendered acidic with a 10% aqueous hydrochloric acid and filtered. The filtrate was again treated with activated carbon followed by concentration. The addition of ethanol to the concentrate gave rise to crystals which were recrystallized from ethanol-water to obtain 1.5 g of 9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]-quinoline-5-carboxylic acid hydrochloride as light yellow needles having a melting point of 300° C. or more.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1.[CH:20](/B(O)O)=[CH:21]\[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Nc1nccc(NCCNc2cc(Cl)nc(N)n2)n1
Product: Nc1nccc(NCCNc2cc(/C=C/c3ccccc3)nc(N)n2)n1

Procedure:
The product of Example 6A (57 mg, 0.203 mmol) and (E)-styrylboronic acid (33 mg, 0.223 mmol) were treated under the conditions described in Example 6B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.48-7.65 (m, 4H) 7.26-7.43 (m, 3H) 6.76-7.02 (m, J=15.86 Hz, 3H) 5.80-5.94 (m, 5H) 5.74 (d, J=5.95 Hz, 1H) 3.34-3.43 (m, 4H); MS (ESI+) m/z 349.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](SC)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1.[CH3:42][C:43]1([CH3:52])[CH2:48][CH:47]([NH2:49])[CH2:46][C:45]([CH3:51])([CH3:50])[NH:44]1>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:49][CH:47]3[CH2:48][C:43]([CH3:52])([CH3:42])[NH:44][C:45]([CH3:51])([CH3:50])[CH2:46]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NCCc1ccc(F)cc1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: Cc1ccc(C(=O)NCCc2ccc(F)cc2)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound is prepared from the acid from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid by following the procedures in Example 19 using 2-(4-fluorophenyl)ethanamine for the amide formation and 2,2,6,6-tetramethyl-4-piperidinamine for the displacement reaction: LC-MS m/z 669 (M+H)+, 2.03 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1.C(OC1C=CC(NC2N=CN=C(OC3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.Cl[C:72](=[O:79])[CH2:73][C:74]([O:76][CH2:77][CH3:78])=[O:75]>CN(C=O)C.CCOC(C)=O>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:72](=[O:79])[CH2:73][C:74]([O:76][CH2:77][CH3:78])=[O:75])=[CH:3][C:4]=2[F:18])[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)picolinamide (Compound B′ of Example 24, 1.0 g, 4.0 mmol) in DMF (10.0 mL) were added DIEA (2.0 mL) and ethyl 3-chloro-3-oxopropanoate (Aldrich, 0.75 mL, 6.0 mmol). The mixture was stirred at room temperature for 12 h and more ethyl 3-chloro-3-oxopropanoate (0.20 mL, 1.6 mmol) was added. The mixture was stirred for 2 h and was then diluted with EtOAc (200 mL). It was washed with H2O and brine and then dried over MgSO4. After filtration and concentration, the residue was triturated with DCM and filtered to give ethyl 3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (900 mg, 62% yield). MS(ESI+) m/z 362.28 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:17][C:18](Cl)=[O:19]>>[C:1]([C:5]1[C:6]([NH:14][C:18](=[O:19])[CH2:17][C:16]([CH3:15])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(=O)Cl)c1ccccc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)CC(C)(C)c2ccccc2)nn2cccnc12

Procedure:
The product from Example 105B and the product from Example 117A were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 1.45 (s, 6H), 2.65 (s, 2H), 6.97 (dd, J=7.1, 4.1 Hz, 1H), 7.15-7.19 (m, 1H), 7.28-7.33 (m, 2H), 7.42-7.44 (m, 2H), 8.46 (dd, J=4.1, 1.7 Hz, 1H), 8.91 (dd, J=7.0, 1.9 Hz, 1H), 9.59 (s, 1H); MS (DCI) m/z 351 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]2[NH:18][N:17]=[CH:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([N:18]1[CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][CH:16]=[N:17]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: C1=NNC(c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1N=CCC1c1ccccc1
Yield: 61.9 %

Procedure:
Triethylamine (2.1 g) was added to a solution of 2.92 g 5-phenyl-2-pyrazoline in 50 ml chloroform, and the mixture was stirred with ice cooling. To the resulting solution, was added dropwise 2.17 g ethyl chloroformate, and the mixture was stirred for one hour. After addition of 50 ml water, the mixture was extracted with 50 ml chloroform, the extract was dried, the dried solution was concentrated, and the residue was purified by silica gel chromatography (chloroform/methanol=100/1), giving 2.7 g (yield: 62%) of pure product as oil. NMR (DMSO-d6): 1.21 (3H, t, J=6 Hz), 2.6-3.7 (2H, m), 4.18 (2H, q, J=6 Hz), 5.22 (1H, dd, J=6, 12 Hz), 6.92 (1H, t, J=2 Hz), 7.1-7.5 (5H, m).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14](O)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].O.[C:26](=[O:29])([O-])[O-].[Na+].[Na+]>>[O:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:14]1[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]3[O:29][C:26]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=3)[CH:6]=2)[CH:1]=1
Reactant: Nc1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: [Na+]
Solvent: O
Product: c1ccc2oc(-c3ccc4cc(-c5nc6ccccc6o5)ccc4c3)nc2c1
Temperature: 70 °C
Yield: 75 %

Procedure:
Synthesis of 2-(2-(benzo[d]oxazole-2-yl)naphthalene-6-yl)benzo[d]oxazole polyphosphoric acid (125 cm3) was heated at 70° C. for 1 hour while agitating. 0.1 mol of naphthalene-2,6-dicarboxylic acid was added and the resulting mixture was stirred for 15 minutes. 0.2 mol of 2-aminophenol was added in a dropwise fashion for 10 minutes. The temperature of the mixture was increased to 150° C. and then this temperature was maintained for 2 hours. The mixture was stirred to cool down to a room temperature. The resulting reaction mixture was stirred for 1 hour with ice water (1.5 dm3), and neutralized with a diluted sodium carbonate hydrate solution. Then it was filtered and dried in an oven for 1 day. The solid was crystallized from dimethylformamide (200 cm3). The final filtered product was rinsed with methanol (100 cm3) and then dried in a 100° C. vacuum oven. As a result, colorless needle-shaped crystalline 2-(2-(benzo[d]oxazole-2-yl)naphthalene-6-yl) benzo[d]oxazole was produced at a yield of 75%.
Reaction SMILES: [Br:1][CH:2]([CH:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(Br)C(Br)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)C(Br)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 50 g of methyl 2,3-dibromo-3-phenylpropanoate, 100 ml of triethylamine and 500 ml of toluene is heated to boiling for 1 h and subsequently cooled to room temperature and filtered. The filtrate is evaporated in vacuo, and the α-bromocinnamic acid obtained in this way is used further without purification. 0.2 mol of the azol derivative dissolved in 150 ml of anhydrous DMF is added dropwise with stirring to a suspension of 4.7 g of NaK (80% in mineral oil) in 100 ml of anhydrous DMF. The temperature of the mixture is maintained below 35° C. during this by cooling with ice. After the addition is complete, the mixture is stirred at room temperature for 1 h. The previously prepared α-bromocinnamic acid is dissolved in 200 ml of anhydrous DMF and, while cooling with ice, the solution of the azol sodium salt is added dropwise with stirring. After stirring at room temperature for two hours, 10.8 ml of glacial acetic acid are added, the mixture is stirred into 1.5 l of ice-water and extracted several times with ethyl acetate, and the organic phases are washed with water. The organic phases are dried and evaporated in vacuo, and the residue is purified by column chromatography on silica gel (mobile phase: n-heptane/ethyl acetate) or recrystallization.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[Cu](C#N)[C:32]#[N:33].O>CN1CCCC1=O>[C:32]([C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30])#[N:33]
Reactant: N#C[Cu]C#N
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1C#N)C2(C)C
Temperature: 110 °C
Reaction time: 24 h
Yield: 4.9 %

Procedure:
2-[5-Bromo-6-oxo-4{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (100 mg, 0.21 mmol) in N-methylpyrrolidone (2.5 mL) was mixed with copper cyanide (100 mg, 1.05 mmol) at room temperature and stirred at 110° C. for 24 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate and chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the desired product (4.3 mg, 5% yield).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH:6]=C.CCO[C:11]([CH3:13])=[O:12].[CH:14]1([Mg]Cl)CCCCC1>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH3:14][C@@:11]1([OH:12])[CH2:13][C@H:6]1[CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCCC=C
Reactant: CCOC(C)=O
Reactant: Cl[Mg]C1CCCCC1
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: C=CCCC[C@@H]1C[C@@]1(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,6-heptadiene (19.65 g, 204 mmol), in THF (341 ml) was added EtOAc (6.67 ml, 68.1 mmol), and chlorotitanium triisopropoxide (68.1 ml, 68.1 mmol). Cyclohexylmagnesium chloride (2M, 153 ml, 306 mmol) was then added slowly over 2 hours. After an additional 1 hour of stirring at RT, the reaction mixture was filtered through CELITE. The filtrate was then concentrated in vacuo and purified on SiO2 (15% EtOAc/hexanes) to yield the title compound as a mixture of enantiomers. To a solution of the enantiomers (5.5 g, 39.2 mmol) in anhydrous DCM, at 0° C. and under N2, was added Et3N (10.9 mL, 78 mmol) and 4-nitrobenzoyl chloride (8.7 g, 47.1 mmol). The reaction was stirred for 2 hours, diluted with H2O (70 mL) and extracted with DCM (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (gradient elution, 0 to 50% EtOAc in hexane) to yield (1R,2R and 1S,2S)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate. The benzoate enantiomers (12 g, 41.5 mmol) were separated by chiral chromatography on an AD-H column, eluting with 10% CO2 in MeOH. The desired peak fractions were concentrated to give (1R,2R)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate. To a solution of (1R,2R)-1-methyl-2-(pent-4-en-1-yl)cyclopropyl 4-nitrobenzoate (4.87 g, 16.83 mmol) in MeOH (67 mL) was added K2CO3 (4.65 g, 33.7 mmol). The mixture was stirred for 1 hour, filtered, and concentrated in vacuo. The material was purified on SiO2 (gradient elution, 0-50% ether/hexanes) to give the title compound. 1H NMR (500 MHz) (CDCl3) δ 5.82 (m, 1H), 4.99 (m, 2H), 2.09 (m, 2H), 1.78 (s, 1H), 1.55 (m, 2H), 1.41 (s, 3H), 1.32 (m, 1H), 1.14 (m, 1H), 0.97 (m, 1H), 0.84 (m, 1H), 0.06 (m, 1H).
Reaction SMILES: C1CCN([C:7](/N=N/C(N2CCCCC2)=O)=[O:8])CC1.O[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[N:25][C:26](OC)=[N:27]2)=[CH:22][CH:21]=1.C1(OCCO)CCCC1.C(P(CCCC)CCCC)CCC.C(Cl)[Cl:55]>CCOCC>[ClH:55].[CH3:7][O:8][C:24]1[C:23]2[C:28](=[CH:29][CH:20]=[CH:21][CH:22]=2)[N:27]=[CH:26][N:25]=1
Reactant: COc1ncc2ccc(O)cc2n1
Reactant: ClCCl
Reactant: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: OCCOC1CCCC1
Solvent: CCOCC
Product: COc1ncnc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60 %

Procedure:
1,1-(Azodicarbonyl)dipiperidine (355 mg, 1.4 mmol) was added in portions to a mixture of 44-chloro-2-fluoroanilino)-7-hydroxy-methoxyquinazoline (I 50 mg, 0.47 mmol), (prepared as described for the starting material in Example 2), 2-(cyclopentyloxy)ethanol (91 mg, 0.7 mmol), (U.S. Pat. No. 4,515,814), and tributylphosphine (284 mg, 1.4 mmol) in methylene chloride (6 ml) at 0° C. The mixture was then allowed to warm to ambient temperature and stirred for 3.5 hours. Ether (3 ml) was added and the insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was dissolved in acetone and 1M ethereal hydrogen chloride (0.6 ml) was added. The mixture was left to stand for 60 hours and the precipitate was collected by filtration, washed with acetone and dried to give 44-chloro-2-fluoroanilino)-72-cyclopentyl xyethoxy)-4-methoxyquinazoline hydrochloride (130 mg, 60%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][N:8](CC(=O)C)[CH2:7][C:6]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:5]1.[CH2:26](N(S(F)(F)F)CC)C.[F-].[Cs+].F[C:38]([F:43])([F:42])[C:39](O)=O>ClCCl>[F:42][C:38]([F:43])([CH3:26])[CH2:39][N:8]1[CH2:9][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[CH2:7]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCC1CN(CC(C)=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: O=C(O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Product: COCC1CN(CC(C)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 2-(methoxymethyl)-4-(2-oxopropyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate in dichloromethane (1 mL) was added and N,N-diethylaminosulfur trifluoride (195 μL, 1.47 mmol). Cesium fluoride (9.0 mg, 0.059 mmol) was then added in two portions followed by trifluoroacetic acid (5 μL, 0.06 mmol). The reaction was stirred for 15 min then cooled to 0° C. and quenched with 5 mL of saturated aqueous NaHCO3. The reaction was diluted with dichloromethane (5 mL) and the layers separated. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated in vacuo to provide tert-butyl 8-(2,2-difluoropropyl)-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate as yellow oil. ESI-MS m/z calc. 378.2. Found 379.3 (M+1)+; Retention time: 1.53 minutes (3 min run).
Reaction SMILES: N[C:2]([C:5]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])=[O:12])[C:8]([OH:26])=[C:7]([OH:27])[N:6]=1)([CH3:4])[CH3:3].[CH2:28]=O.[C:30]([BH3-])#[N:31].[Na+]>C(OC)(OC)OC.C(O)(=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:9]2[N:10]=[C:5]3[C:2]([CH3:3])([CH3:4])[N:31]([CH3:30])[CH2:28][N:6]3[C:7](=[O:27])[C:8]=2[OH:26])=[O:12])=[C:16]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:17]=1
Reactant: C=O
Reactant: CC(C)(N)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)n1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CN1Cn2c(nc(C(=O)NCc3ccc(F)cc3S(C)(=O)=O)c(O)c2=O)C1(C)C
Reaction time: 1 h

Procedure:
2-(1-amino-1-methylethyl)-N-[4-fluoro-2-(methylsulfonyl)benzyl]-5,6-dihydroxypyrimidine-4-carboxamide (prepared as described in WO2003035076 A1) was taken in trimethyl orthoformate and treated with 1.1 eq. of formaldehyde. The mixture was aged at room temperature for 1 hour, and then an additional equivalent of formaldehyde was added, followed by 1.5 eq. of sodium cyanoborohydride and a few drops of acetic acid. Stirring was continued for one hour more, and the mixture was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]1[O:16][C:15]2[CH:14]=[CH:13][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3)=[CH:4][C:3]=2[O:2]1.[O:17]=[C:18]1[CH:22]([CH2:23][C:24]([Cl:26])=[O:25])[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=2[O:19]1>C1C=CC=CC=1>[ClH:26].[O:17]=[C:18]1[CH:22]([CH2:23][C:24]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:13]=[CH:14][C:15]4[O:16][CH2:1][O:2][C:3]=4[CH:4]=3)[CH2:8][CH2:9]2)=[O:25])[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=2[O:19]1
Reactant: O=C(Cl)CC1C(=O)Oc2ccccc21
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Solvent: c1ccccc1
Product: Cl
Product: O=C1Oc2ccccc2C1CC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
A solution of 9.4 g of 4-(3,4-methylenedioxybenzyl)piperazine in 100 ml of anyhydrous benzene is added to a solution, cooled beforehand to 10° C., of 4.5 g of 2-(2,3-dihydro-2-oxo-3-benzofuranyl)acetyl chloride in 50 ml of anhydrous benzene. The mixture is stirred for 12 hours at room temperature and the precipitate of amine hydrochloride is filtered off and washed several times with benzene. The combined organic phases are washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product obtained is chromatographed on 300 g of 70-230 mesh silica (eluant: dichloromethane/methanol 9.5:2.5 V/V). The resulting product (3 g) is dissolved in the minimum amount of acetone and crystallized in the form of the hydrochloride by adding 1.5 ml of 5.07N ethanolic hydrochloric acid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[O:1]([C:8]1[CH:9]=[C:10]([NH:11][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([OH:15])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
The 3-(phenoxy)aniline (555 mg, 3 mmol) and 3-hydroxybenzaldehyde (366 mg, 3 mmol) were dissolved in 7 mL of 1,2-dichloroethane. Acetic acid (0.189 mL 3.15 mmol) and solid NaBr(OAc)3 (1.01 g, 5 mmol) were added. The mixture was stirred at room temperature for 3 h, then acidified with 1NHCl solution. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 609 mg (69%) of the desired N-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=291.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[O-:13][Mn](=O)(=O)=O.[K+].[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>>[CH2:19]([N:21]1[C:22](=[O:23])[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:13])[S:11]1)[CH3:20]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: S=C=NCCc1ccccc1
Reactant: CCN=C=O
Agent: Cl
Agent: [K+]
Product: CCn1sc(=O)n(CCc2ccccc2)c1=O

Procedure:
Reagents: phenethyl isothiocyanate (0.97 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isocyanate (0.51 ml, 6.5 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(O)C>[F:23][C:20]([F:21])([F:22])[C:19]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:16]=[N:17][N:18]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1nnnn1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A solution of 129 g (0.40 mol) of 1-(4-benzyloxyphenyl)-5-trifluoromethyl-1H-tetrazole in 900 mL 1:2 THF/ethanol was hydrogenated at ambient temperature over 6 g 10% Pd/C at 45 psi hydrogen for 12 h. The catalyst was removed by filtration through Celite®, the cake washed with ethanol, and the filtrate concentrated. The product was dissolved in ether, filtered through magnesium sulfate and concentrated. During concentration the product began to crystallize, as the product crystallized the mixture was flushed with hexanes to remove the ether. The resulting slurry was cooled to 0° C., aged 1 hr, filtered, and the cake washed with hexanes. The yield upon drying was 84.8 g (91.5%) of white crystalline 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol: 1H NMR (CDCl3) δ 5.6 (s, 1H), 7.07 (m, 2H), 7.35 (m, 2H). MS (EI) m/z 230. Anal. Calcd for C8H5F3N4O: C, 41.75; H, 2.19; F, 24.76; N, 24.34. Found: C, 41.76; H, 2.23; F, 24.53; N, 24.42. KF <0.1%.